For many years, barbiturates were the most commonly used drugs in the treatment of symptomatic anxiety. The discovery of the benzodiazepine nucleus by Sternbach and his colleagues led to the development of chlordiazepoxide, the first member of a group, which was shown to be highly effective with few side effects. Within a few years of their introduction in 1960, the benzodiazepines have effectively replaced barbiturates as the drugs of choice in anxiety and insomnia and their additional use as anti-convulsants and muscle relaxants added to their clinical and commercial potential.
The benzodiazepines exert most of their pharmacological effects by a selective facilitation of the postsynaptic actions of gamma-aminobutyric acid (hereinafter "GABA"). A number of clinical, behavioral and electrophysiological studies have demonstrated that the chronic administration of benzodiazepines, results in tolerance to the sedative, muscle relaxant and anticonvulsant properties of the drug. Although the cellular basis for these behavioral changes is not well understood, present knowledge of benzodiazepine receptor functions points to involvement of GABAergic processes. It is well known, for example, that acutely administered benzodiazepines selectively enhance postsynaptic GABAergic neurotransmission. However, prolonged exposure to benzodiazepines in vivo and in vitro markedly attentuates this facilitory effect. Classic tolerance is normally followed by escalation in dosage to maintain the drug's pharmacological effects. An escalation in dosage, however, is undesirable.
Upon development of tolerance, the continued administration of the benzodiazepines is not beneficial. The cessation of administration, however, often leads to withdrawal syndrome. The first symptoms experienced in a withdrawal syndrome are identical to those of anxiety, including apprehension, somatic complaints such as nausea and palpitations and tension. It has been known for many years that patients often experience anxiety after reduction of benzodiazepine intake. The withdrawal reaction develops into a characteristic abstinence syndrome with specific symptoms which cannot be explained by anxiety alone. The time course of each condition also differs. When a drug is stopped, symptoms can remain as they are (neutral reaction), become steadily worse after withdrawal until they reach a plateau of higher symptomatology (anxiety reactions) or increase temporarily before returning to their original level (withdrawal reaction).
When benzodiazepines that have been taken long term in regular dosage are stopped, there is a variable period of hours to several days before adverse effects appear. This variability occurs because of the accumulation of benzodiazepine drugs and their active metabolites during the long-term administration. The amount of accumulation with multiple dosage depends on the elimination half life of the drug and its metabolites, being less with the compounds of short half life. The period of onset of withdrawal reactions is therefore dependent on the drug half life. The duration of the withdrawal reaction is also variable and can last up to twenty days. The temporary prescription of other drugs, particularly beta blockers, may attentuate the withdrawal symptoms.
As is apparent, there is a continuing need for an effective agent which will prevent benzodiazepine withdrawal symptoms and a continuing need for an agent which will regenerate the sensitivity response to and prevent tolerance of benzodiazepines which are chronically administered.
The need for a drug which could reverse some or all of the effects of benzodiazepines has occasionally been expressed by clinicians. Indications proposed for such an "antidote" include the selective reduction of the sedative effects in patients who require high doses of benzodiazepines for the treatment of severe muscular spasticity, the reversal of sedation and anterograde amnesia in surgical patients operated on using balanced anesthesia containing benzodiazepines and from whom informed consent is required for an urgent subsequent surgical intervention, the treatment of accidental overdosages in children and the treatment of suicidal intoxication in adults. As a result of the perceived need, a series of benzodiazepine antagonist have been developed. See, e.g., Haefley et al, Benzodiazepines Antagonists, The Benzodiazepine: From Molecular Biology to Clinical Practice (Costa, Ed. Raven Press, New York, 1983), pp. 137-146. A particularly effective benzodiazepine antagonist is flumazepil, ethyl-8-fluoro-5,6,dihydro-5-methyl-6-oxo-4H-imidazo [1,5a](1,4)benzodiazepine-3-carboxylate; also known as Ro 15-1788. See, e.g., Darragh et al, Absence of Central Effects in Man of the Benzodiazepine Antagonist Ro 15-1788, Pharmacology (1983) 80: 192-195 and Klotz et al, Pharmakinetics of the Selective Benzodiazepine Antagonist Ro 15-1788 in Man, Eur. J. Clinic. Pharmacol. (1984) 27:115-117.
In an article that I co-authored with J.M. Lakoski, S. F. Gonsalves and S. L. Rauch, Chronic Benzodiazepine Treatment Decreases Postsynaptic GABA Sensitivity, Nature, Vol. 308, No. 5954, pp. 74-77, Mar. 1, 1984, we point out that acute injection of flumazepil reversed rapidly the decrease in GABA sensitivity observed in chronically diazepam treated animals without altering GABA sensitivity in vehicle treated animals. Since flumazepil is well known to have an extremely short half life, on the order of about 15 minutes in rats, it was believed that the reversal was transitory and very short lived. In humans, flumazepil has a half life of approximately 1 hour (Klotz, et al, 1984). By way of comparison the benzodiazepine agonist, triazolam, has an elimination half life of 2-5 hours and is considered to have an ultra short half life when compared to other benzodiazepines.
I have now determined that a single exposure to benzodiazepine antagonists like flumazepil actually reverses benzodiazepine tolerance completely and persistently, an event which is correlated with an alteration in the GABA receptor complex back to its pre-drug state. This is different from direct antagonism at the benzodiazepine receptor site which occurs when sufficient quantities of antagonists are present in the system to competitively displace the agonist (i.e. the benzodiazepine). It is believed that tolerance to benzodiazepines is due to an alteration in the GABA-benzodiazepine receptor complex and that the antagonist shifts the altered complex back to its normal, agonist-native state. Since tolerance develops over a protracted time period, effective clinical prevention of tolerance can be achieved by the periodic exposure to antagonist during the course of active benzodiazepine exposure before significant tolerance develops. It has also been determined that such periodic administration of the antagonist prevents withdrawal lability. In seizure disorders in which chronic benzodiazepine administration is efficacious but limited by tolerance development, the periodic administration of the antagonist would allow continued effective treatment with the benzodiazepines a would the anti-spastic effects following chronic benzodiazepine treatment. In panic disorders, where some benzodiazepine analogs have been shown to be efficacious, periodic administration of antagonists would prevent tolerance development and withdrawal lability.
It is, accordingly, the object of this invention to provide a method for regenerating sensitivity of response and thereby preventing tolerance to benzodiazepines, particularly during chronic benzodiazepine and also to provide a method of preventing benzodiazepine withdrawal symptoms. These and other objects of the invention will be apparent to those skilled in the art from the following detailed description in which FIGS. 1 and 2 are histograms of mean IxT.sub.50 values and FIGS. 3 and 4 are histograms of bicuculline seizure threshold values.